Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot,Randomized, Double‐Blinded,Placebo‐Controlled Clinical Trial

Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24–48 h before the initiation of cisplatin infusion and continuing to the end of three 21‐day cisplatin‐containing chemotherapy courses on cisplatin‐induced renal electrolytes wasting and kidney function were assessed. Cisplatin‐associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase‐associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin‐induced urine electrolyte wasting or renal function impairment. Copyright © 2015 John Wiley & Sons, Ltd.     

Effects of naringenin and silymarin on urinary excretion of water and electrolytes in rats

The effects of two flavonoid derivatives, naringenin and silymarin on urinary excretion of water and electrolytes were investigated in isotonic saline loaded rats. Both compounds, especially naringenin, showed a moderate diuretic activity, in comparison with furosemide, increasing significantly the renal loss of sodium, chloride and potassium. With respect to silymarin, although urinary excretion was significantly lower, it caused a marked decrease in potassium excretion. These results indicate that naringenin has a diuretic behaviour similar to moderate-efficiency diuretic agents and silymarin to potassium-sparing diuretics.     

The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial

Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either cause direct pancreatic beta-cell damage or lead to metabolic abnormalities that can induce or aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported in experimental and clinical studies. The present study was designed to investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA(1)c), fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the beginning and the end of the study. The results showed a significant decrease in HbA(1)c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.     

Topical delivery of silymarin constituents via the skin route

Aim:

Silibinin (SB), silydianin (SD), and silychristin (SC) are components of silymarin. These compounds can be used to protect the skin from oxidative stress induced by ultraviolet (UV) irradiation and treat it. To this end, the absorption of silymarin constituents via the skin was examined in the present report.

Methods:

Transport of SB, SD, and SC under the same thermodynamic activity through and into the skin and the effects of pH were studied in vitro using a Franz diffusion assembly.

Results:

The lipophilicity increased in the order of SCsilymarin constituents in the less-ionized form, but it did not affect deposition within the skin. With in vivo topical application for 4 and 8 h, the skin deposition of SB was higher than those of SD and SC by 3.5∼4.0- and 30∼40-fold, respectively. The skin disruption and erythema test demonstrated that the topical application of these compounds for up to 24 h caused no apparent skin irritation.

Conclusion:

The basic profiles of silymarin permeation via skin route were established.     

Olanzapine-induced hepatopathy in albino rats: A newer model for screening putative hepatoprotective agents, namely silymarin

Backgrounds:

This study was conducted to establish olanzapine-induced hepatopathy in Wistar albino rats as a newer model to screen putative hepatoprotective agents namely silymarin.

Materials and Methods:

Albino rats were divided into three groups, namely vehicle control group (CG), olanzapine-treated group (OZ), and olanzapine plus silymarin (OZS) treated groups. Both the OZ and OZS groups were treated with the same dose of intraperitoneal olanzapine for 6 weeks and group OZS additionally received oral silymarin. Baseline and terminal hepatic enzymes (SGOT, SGPT, and ALP) were measured in all three groups.

Results:

Histopathological examination of livers of both OZ and OZS groups showed degenerative changes, whereas those of control group showed normal architecture. Liver enzyme levels showed statistically significant rise in comparison to the control group as well as the respective base line values in both the test groups, but the differences in the rise of liver enzymes between the two test groups were not statistically significant.

Conclusion:

Olanzapine-induced hepatopathy in rats can be used as a model for screening putative hepatoprotective agents and in our setting silymarin has failed to provide any hepatoprotection.     

Antioxidant and hepatoprotective activities of Egyptian moraceous plants against carbon tetrachloride-induced oxidative stress and liver damage in rats

Context: In the absence of reliable liver-protective drugs in modern medicine, a large number of medicinal preparations are recommended for treatment of liver disorders.

Objective: The antioxidant, hepatoprotective and kidney protective activities of methanol extracts of Ficus carica Linn. (Moraceae) leaves and fruits and Morus alba Linn. root barks (Moraceae) are evaluated here.

Materials and methods: Liver and kidney damage were induced in rats by carbon tetrachloride in a subcutaneous dose of 1?mL (40% v/v in corn oil)/kg. The extract was given intraperitoneally at doses of 50?mg/kg (F. carica leaf and M. alba root bark) and 150?mg/kg (F. carica fruit). The activity of the extracts was comparable to that of silymarin, a known hepatoprotective agent. Antioxidant activity was evaluated by measuring blood glutathione (GSH) content, superoxide dismutase (SOD), catalase (CAT) activities, and malondialdehyde equivalent (MDA). Hepatoprotective activity was evaluated by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and total protein. These biochemical observations were supported by histopathological examination of liver sections. Kidney function was evaluated by measuring plasma urea and creatinine.

Results: Methanol extracts of Ficus carica and Morus alba showed potent antioxidant and hepatoprotective activities; in-depth chromatographic investigation of the most active extract (Ficus carica leaf extract) resulted in identification of umbelliferone, caffeic acid, quercetin-3-O-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranoside, and kaempferol-3-O-α-l-rhamnopyranoside.

Discussion and conclusion: These findings demonstrate that the phenolic constituents of Ficus carica leaf and Morus alba root bark are responsible at least in part for the observed protective effects.     

Investigation of a Novel Multicomponent Mycotoxin Detoxifying Agent in Amelioration of Mycotoxicosis Induced by Aflatoxin-B1 and Ochratoxin A in Broiler Chicks

The present study was designed to determine the efficacy of a novel multicomponent mycotoxin detoxifying agent (MMDA) containing modified zeolite (Clinoptilolite), Bacillus subtilis, B. licheniformis, Saccharomyces cerevisiae cell walls and silymarin against the deleterious effects of Aflatoxin B₁ (AFB₁) and Ochratoxin A (OTA) in broiler chicks. A total of 160 one-day-old Ross 308^® broiler chicks were randomly allocated in four treatment groups, with four replicates, according to the following experimental design for 42 days. Group A received a basal diet; Group B received a basal diet contaminated with AFB₁ and OTA at 0.1 mg/kg and 1 mg/kg, respectively; Group C received a basal diet contaminated with AFB₁ and OTA and MMDA at 1 g/kg feed, and Group D received a basal diet contaminated with AFB₁ and OTA and MMDA at 3 g/kg feed. Results showed that ingested mycotoxins led to significant (p ≤ 0.05) reduction in body weight and feed conversion from 25 days of age, induced histopathological changes, increased the pH of the intestinal content, and altered the biochemical profile of birds with significantly (p ≤ 0.05) increased aspartate aminotransferase (AST) values (p ≤ 0.05). On the other hand, the supplementation of MMDA significantly (p ≤ 0.05) improved the feed conversion ratio (FCR) during the second part of the study, diminished biochemical alterations, reduced pH in jejunal and ileal content, and E. coli counts in the caeca of birds (p ≤ 0.05). It may be concluded that the dietary supplementation of the MMDA partially ameliorated the adverse effects of AFB₁ and OTA in broilers and could be an efficient tool in a mycotoxin control program.     

Metabolic effect of berberine–silymarin association: A meta‐analysis of randomized,double‐blind,placebo‐controlled clinical trials

The aim of this study is to assess the impact of a combination of berberine and silymarin on serum lipids and fasting plasma glucose (FPG) through a systematic review of literature and meta‐analysis of the available randomized, double‐blind, placebo‐controlled clinical trials (RCTs). A systematic literature search in SCOPUS, PubMed‐Medline, ISI Web of Science, and Google Scholar databases was conducted up to October 2, 2018, in order to identify RCTs assessing changes in plasma concentrations of total cholesterol (TC), triglycerides (TG), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C) and FPG during treatment with berberine and silymarin in combination. Two review authors independently extracted data on study characteristics, methods, and outcomes. Quantitative data synthesis was performed using a random‐effects model. We identified five eligible RCTs, with 497 subjects overall included. Berberine and silymarin combination treatment exerted a positive effect on TC (mean difference [MD]: ?25.3, 95% CI [?39.2, ?11.4] mg/dl; p < 0.001), TG (MD: ?28, 95% CI [?35.3, ?20.6] mg/dl; p < 0.001), HDL‐C [MD: 6, 95% CI [3.2, 8.8] mg/dl; p < 0.001), LDL‐C (MD: ?29.1, 95% CI [?39.7, ?18.6] mg/dl; p < 0.001), and FPG (MD: ?7.5, 95% CI [?13, ?1.9] mg/dl; p = 0.008). The present findings suggest that the coadministration of berberine and silymarin is associated with an advantageous improvement in lipid and glucose profile, suggesting the possible use of this nutraceutical combination in order to promote the cardiometabolic health.     

CPT11 with P-glycoprotein/CYP 3A4 dual-function inhibitor by self-nanoemulsifying nanoemulsion combined with gastroretentive technology to enhance the oral bioavailability and therapeutic efficacy against pancreatic adenocarcinomas

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life (T_1/2) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.